Treatments for neurogenetic disorders, impulse control disorders, and wound healing

ABSTRACT

The subject invention provides methods and compositions for the treatment of neurogenetic disorders, particularly DSM-IV impulse control disorders such as intermittent explosive disorder, kleptomania, pyromania, pathologic gambling, trichotillomania, and other impulse control disorders such as compulsive buying and problematic Internet use. In a preferred embodiment, the subject invention provides methods for treating or controlling symptoms associated with ADHD or PWS comprising the administration of therapeutically effective amounts of compositions containing compounds of the formulas I-V. In another embodiment, the subject invention provides for methods of promoting wound healing comprising the administration of a therapeutically effective amount of a composition comprising the compounds of formulas I-V. Compositions may administered to a wound site via a salve, ointment, or as a component of a bandage or bioadhesive applied to the site of injury. The invention also provides therapeutically effective compositions comprising one or more of the compounds of formulas I-V.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.09/997,447, filed Nov. 30, 2001,which claims the benefit of U.S.Provisional Application No. 60/250,113, filed Nov. 30, 2000, both ofwhich are hereby incorporated by reference herein in their entireties,including any figures, tables, or drawings.

BACKGROUND OF THE INVENTION

As many as one-third of the approximate 3,000 known genetic disordersare believed to have important neurological involvement. Individually,most genetic disorders are of low incidence in the general population;however, collectively they represent an enormous burden on affectedindividuals, their families, and society. Many neurogenetic disordersmanifest themselves early in life leading to either a premature death orto lifelong disability with significant attendant psychological andeconomic hardships.

Examples of these types of disorders include: (1) Hereditary ataxias andrelated disorders such as Friedreich ataxia, ataxia telangiectasia,olivopontine cerebellar degeneration, Ramsay Hunt syndrome,abetalipoproteinemia, Machado-Joseph disease, and familial spasticparaparesis; (2) Movement disorders such as Juvenile Huntington disease,the dystonias including blepharospasm and spasmodic torticolis, tremor,myoclonus, and Hallervorden-Spatz disease; (3) Phakomatoses, orneurocutaneous syndromes such as neurofibromatosis, tuberous sclerosis,Sturge-Weber, and Von Hippel-Landau disease; (4) Mitochondrialencephalomyopathies such as the MELAS syndrome, Keams-Sayre, and Leighdisease; (5) Hereditary disorders of nerve and muscle such as infantilespinal muscular atrophy, Charcot-Marie-Tooth disease, hereditary sensoryand autonomic neuropathies, genetic myasthenic syndromes, metabolicmyopathies, muscular dystrophies, and myotonias.

There are numerous other neurological disorders that are also believedto result from genetic abnormalities such as theLaurence-Moon-Bardet-Biedl, Aicardi, Sjogren-Larsson, Prader-Willi andAngelman syndromes.

In addition to those diseases that have a recognizable pattern ofinheritance, there are many other neurological disorders that seem tohave, in some cases, a familial basis. These may well representneurogenetic disorders with multifactorial etiology. Such diseases canbe as diverse as disorders of defective cellular migration (such aslissencephaly, heterotopias), neural tube defects, congenitalhydrocephalus, myoclonic epilepsy, attention deficit hyperactivitydisorder (ADHD), and narcolepsy.

It is estimated that ADHD affects about 4% to 6% of the U.S. population.ADHD is not limited to children and is a chronic lifetime disease.Approximately one-half to two-thirds of children with ADHD will continueto have significant problems in adulthood and experience difficultieswhich impact employment, familial, and social relationships.

According to the DSM-IV (the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition) some common symptoms of ADHD include: (1)often fails to give close attention to details or makes carelessmistakes; (2) often has difficulty sustaining attention to tasks; (3)often does not seem to listen when spoken to directly; (4) often failsto follow instructions carefully and completely; (5) losing orforgetting important things; (6) feeling restless, often fidgeting withhands or feet, or squirming; (7) running or climbing excessively; (8)often talks excessively; (9) often blurts out answers before hearing thewhole question; and (10) often has difficulty awaiting turn. It shouldbe kept in mind that the exact nature and severity of ADHD symptomsvaries from person to person however. Approximately one-third of peoplewith ADHD do not have the hyperactive or overactive behavior component.

To meet diagnostic criteria, these behaviors must be excessive,long-term, and pervasive. The behaviors must appear before age 7, andcontinue for at least 6 months. A crucial element requires that thebehaviors must create a real handicap in at least two areas of aperson's life, such as school, home, work, or social settings. Thesecriteria set ADHD apart from the “normal” distractibility and impulsivebehavior of childhood, or the effects of the hectic and overstressedlifestyle prevalent in our society.

There are no reports in the literature of topiramate specifically usedto treat deficits in attention and concentration. Carbamazepine(Tegretol) has been reported to be useful for the treatment of patientsexperiencing sudden confusion and depression. Within weeks of initiatingtreatment, the patients experienced fewer incidences of sudden confusionand depression, and an increase in attention and focus. Persinger, M.A., “Subjective improvement following treatment with carbamazepine(Tegretol) for a subpopulation of patients with traumatic braininjuries”, Percept Mot Skills 90:37-40 (2000). Carbamazepine has alsobeen shown to be effective in treating children with features of ADHD.Silva, R. R.; Munoz, D. M.; Alpert, M., “Carbamazepine use in childrenand adolescents with features of attention-deficit hyperactivitydisorder: a meta-analysis”, J Am Acad Child Adolesc Psychiatry35:352-358 (1996). In some patients, with or without intellectualdisability, being treated for refractory partial epilepsy, gabapentin isan equally effective add-on medication. Mikati, M. A.; Choueri, R.;Khurana, D. S.; et al., “Gabapentin in the treatment of refractorypartial epilepsy in children with intellectual disability”, J IntellectDisabil Res 42:57-62 (suppl. 1, 1998). Three dementia patients are notedin the literature to have received topiramate in a retrospective chartreview of 58 consecutive psychiatric patients receiving topiramate.Marcotte, D., “Use of topiramate, a new anti-epileptic as a moodstabilizer”, J Affect Disorder 50:245-251 (1998). “Improvement” wasrated by a Likert scale from ‘worse,’ to ‘no change,’ to ‘minimallyimproved,’ to ‘moderately improved,’ to ‘markedly improved.’ The threepatients with dementia are described to have ‘moderate’ or ‘marked’improvement when on topiramate. The author of this chart reviewhypothesized that topiramate may have some anti-psychotic effect.

While there have been no reported efforts to use topiramate for thetreatment of impulsivity, there have been a limited number ofpublications reporting the effects of anti-convulsant treatment onimpulsivity (or measures of impulsivity). These references tend to showno change or worsening of impulsivity with anti-convulsant treatment.For example, one large study showed no overall effect on measures ofimpulsivity of anti-convulsant medication in epileptic children(Mitchell, W. G.; Zhou, Y.; Chavez, J. M.; Guzman, B. L., “Reactiontime, attention, and impulsivity in epilepsy”, Pediatr Neurol 8:19-24(1992)) and another large study showed, at higher total serum levels ofanti-convulsant medication in children with epilepsy, more impulsiveerrors on complex reaction time testing (Mitchell, W. G.; Zhou. Y.;Chavez, J. M.; Guzman, B. L., “Effects of anti-epileptic drugs onreaction time, attention, and impulsivity in children”, Pediatrics91:101-105 (1993)). It is notable that both of these studies focused onchildren with epilepsy.

A case report from 1987 described carbamazepine being useful forintermittent explosive disorder in a patient with Prader-Willi Syndrome(Gupta, B. K.; Fish, D. N.; Yerevanian, B. I., “Carbamazepine forintermittent explosive disorder in a Prader-Willi syndrome patient”, JClin Psychiatry 48:423 (1987)). Carbamazepine has also been reporteduseful in the treatment of pathological gambling (Haller, R.;Hinterhuber, H., “Treatment of pathological gambling withcarbamazepine”, Pharmacopsychiatry 27:129 (1994)). There are alsoreports in the literature of divalproex being effective for explosivemood and mood lability (Donovan, S. J.; Stewart, J. W.; Nunes, E. V.;Quitkin, F. M.; Parides, M.; Daniel, W.; Susser, Klein D. F.,“Divalproex treatment for youth with explosive temper and mood lability:a double-blind, placebo-controlled crossover design”, Am J Psychiatry157:818-820 (2000)) and for a patient with kleptomania and mixed mania(Kmetz, G. F.; McElroy, S. L.; Collin, D. J., “Response of kleptomaniaand mixed mania to valproate”, Am J Psychiatry 154:580-581 (1997)).

Prader-Willi Syndrome (PWS) is a neurogenetic multisystem disordercharacterized by infantile hypotonia, mental retardation, short stature,hypogonadism, dysmorphic features, and hyperphagia with a high risk ofobesity. Also very common in PWS are behavioral and psychiatricmanifestations. These include self-injury (e.g. gouging, nail biting,and skin picking), explosive outbursts, oppositional behavior, obsessiveruminations, and compulsive behaviors including hoarding, counting, andarranging. PWS is typically a sporadic condition, which usually resultsfrom a deletion in chromosome 15q11-q13 or maternal uniparental disomyof chromosome 15. Glenn, C. G.; Driscoll, D. J.; Thomas, P. Y.;Nicholls, R. D., “Genomic imprinting: potential function and mechanismsrevealed by the Prader-Willi and Angelman syndromes”, Mol Hum Reprod3:321-332 (1997).

PWS is also a relatively common genetic condition with an estimatedprevalence of approximately 1/10,000 to 1/25,000. Glenn, C. G.;Driscoll, D. J.; Thomas, P. Y.; Nicholls, R. D., “Genomic imprinting:potential function and mechanisms revealed by the Prader-Willi andAngelman syndromes”, Mol Hum Reprod 3:321-332 (1997). It was firstdescribed in 1956 (Prader, A.; Labhart, A.; Willi, H., “Ein Syndrome vonadipositas, Kleinwuchs, Kryptorchismus und Oligophrenic nachmyoteniertigem zusland in neugeborenanalter”, Schwiez Med Wschr86:1260-1 (1956)), and the physical problems (such as the obesityrelated cardiovascular diseases, diabetes mellitus, etc.) and behavioralproblems result in the major causes of morbidity and mortality. Martin,A.; Matthew, S.; Koenig, K.; et al., “Prader-Willi syndrome”, Am JPsychiatry 155:1265-1273 (1998).

Treatment for the physical, behavioral, and psychological problemsassociated with PWS is complex. The mainstay of treatment for behavioralproblems including hyperphagia is behavioral modification includingstrategies such as token economies or star systems. Dykens, E. M.;Hodapp, R. M., “Treatment issues in genetic mental retardationsyndromes”, Professional Psychology: Research and Practice 28:263-270(1997). Additionally, medication management of individuals with PWS hasbeen demonstrated to have benefit. Growth hormone therapy in childrenwith PWS can increase muscle tone and enhance growth. Carrel, A. L.;Myers, S. C.; Whitman, B. Y.; et al., “Growth hormone improves bodycomposition, fat utilization, physical strength and agility, and growthin Prader-Willi syndrome: A controlled study”, J Pediatr 134:215-221(1999); Lindgren, A. C.; Hagenas, L.; Muller, J.; et al., “Effects ofgrowth hormone treatment on growth and body composition in Prader-Willisyndrome: a preliminary report”, The Swedish National Growth HormoneAdvisory Group. Acta Paediatr Suppl 423:60-62 (1997). Therefore, growthhormone can help to normalize body habitus. Martin, A.; Matthew, S.;Koenig, K.; et al., “Prader-Willi syndrome”, Am J Psychiatry155:1265-1273 (1998); Carrel, A. L.; Myers, S. C.; Whitman, B. Y.; etal., “Growth hormone improves body composition, fat utilization,physical strength and agility, and growth in Prader-Willi syndrome: Acontrolled study”, J Pediatr 134:215-221 (1999); Lindgren, A. C.;Hagenas, L.; Muller, J.; et al., “Effects of growth hormone treatment ongrowth and body composition in Prader-Willi syndrome: a preliminaryreport”, The Swedish National Growth Hormone Advisory Group. ActaPaediatr Suppl 423:60-62 (1997). In terms of obesity, the anorecticfenfluramine was shown to be helpful for weight loss and aggressivebehavior in PWS utilizing a double-blind placebo-controlled trial.Selikowitz, M.; Sunman, J.; Pendergast, A.; et al., “Fenfluramine inPrader-Willi syndrome: a double-blind, placebo controlled trial”, ArchDis Childhood 65:112-114 (1990). Unfortunately due to cardiovascularconsequences, fenfluramine is not now currently available. There are fewstudies of anorectic agents in PWS and anecdotal reports have beendiscouraging in terms of their benefits. Martin, A.; Matthew, S.;Koenig, K.; et al., “Prader-Willi syndrome”, Am J Psychiatry155:1265-1273 (1998).

Pathological skin picking (PSP) is a severe and chronic psychiatric anddermatologic problem with an average age of onset around 15 years of ageand mean duration of illness of 21 years. Keuthen, W. S.; Deckersbach,T.; Engelhard, I. M.; et al., “Self-injurious skin picking: clinicalcharacteristics and comorbidity”, J Clin Psychiatry 60:454-459 (1999).PSP can lead to significant suffering, dysfunction, and disfigurement.Ko, S. M., “Under-diagnosed psychiatric syndrome II: Pathologic skinpicking”, Ann Acad Med Singapore 28:557-559 (1999). Furthermore, thereis often psychiatric comorbidity. Keuthen, W. S.; Deckersbach, T.;Engelhard, I. M.; et al., “Self-injurious skin picking: clinicalcharacteristics and comorbidity”, J Clin Psychiatry 60:454-459 (1999).PSP is often considered an obsessive compulsive spectrum disorder(Goldsmith, T. D.; Shapira, N. A.; Phillips, K. A.; et al., “ObsessiveCompulsive Spectrum Disorders”; in: Swinson, R. P.; Antony, M. M.;Rachman, S.; Richter, M. A. (Eds)., Obsessive-Compulsive Disorder:Theory, Research, and Treatment, Guilford Publications, New York,pp.397-425 (1998)) and, as such, there are several reports of serotoninreceptor inhibitors (SSRI) medication being helpful. Ko, S. M.,“Under-diagnosed psychiatric syndrome II: Pathologic skin picking”, AnnAcad Med Singapore 28:557-559 (1999).

The literature points to topiramate having a negative impact oncognitive functioning including impaired concentration, attention,memory, slowed thinking, word finding, and verbal fluency. Thompson, P.J.; Baxendale, S. A.; Duncan, J. S.; et al.; “Effects of topiramate oncognitive function”, J Neurol Neurosurg Psychiatry 69:636-641 (2000);Privitera, M.; Fincham, R.; Penry, J.; et al., “Topiramateplacebo-controlled dose-ranging trial in refractory partial epilepsyusing 600-, 800-, and 1,000-mg daily dosages”, Topiramate YE StudyGroup. Neurology 46:1678-1683 (1996); Crawford, P., “An audit oftopiramate use in a general neurology clinic”, Seizure 7:207-211 (1998);Jones, M. W., “Topiramate-safety and tolerability”, Can J Neurol Sci25:S13-15 (1998); Burton, L. A.; Harden, C., “Effect of topiramate onattention”, Epilepsy Res 27:29-32 (1997); Martin, R.; Kuzniecky, R.; Ho,S. “Cognitive effects of topiramate, gabapentin, and lamotrigine inhealthy young adults”, Neurology 52:321 (1999); Fraught, E.; Wilder, B.J.; Ramsay, R. E.; et al., “Topiramate placebo-controlled dose-rangingtrial in refractory partial epilepsy using 200-, 400-, and 600-mg dailydosages,” Neurology 46:1684-1690 (1996); and Rosenfeld, W. E.; Liao, S.;Kramer, L. D.; et al., “Comparison of the steady-state pharmacokineticsof topiramate and valproate in patients with epilepsy during monotherapyand concomitant therapy”, Epilepsia 38:324-333 (1997). A few studieshave systematically looked at cognitive changes using neuropsychologicaltesting. In one study (Burton, L. A.; Harden, C., “Effect of topiramateon attention”, Epilepsy Res 27:29-32 (1997)), 10 adult patients withepilepsy were evaluated weekly for up to 13 weeks via a digit span test.In 4 patients, there was an inverse correlation between topiramate doesand test performance. In another study, healthy volunteers were treatedwith topiramate, gabapentin, or lamotrigine for 4 weeks. Impairedcognitive functioning (attention and word fluency) was seen in thetopiramate treated subjects and not in gabapentin or lamotrigine inthese healthy young adults. Martin, R.; Kuzniecky, R.; Ho, S. “Cognitiveeffects of topiramate, gabapentin, and lamotrigine in healthy youngadults”, Neurology 52:321 (1999). Finally, in a recent study of 18epilepsy patients treated with topiramate and receiving repeatneuropsychological assessments, patients on topiramate showedsignificant deterioration in many cognitive domains, including verbalIQ, verbal fluency, and verbal learning. Thompson, P. J.; Baxendale, S.A.; Duncan, J. S.; et al.; “Effects of topiramate on cognitivefunction”, J Neurol Neurosurg Psychiatry 69:636-641 (2000). Improvementin verbal fluency, verbal learning, and digit span increased in patientswhere topiramate was withdrawn or reduced.

The subject invention has, surprisingly, found improvements inimpulsivity control, without negative effects on attention andconcentration, in patients treated with topiramate. These observationsare unexpected and novel.

BRIEF SUMMARY OF THE INVENTION

The subject invention provides methods and compositions for thetreatment of neurogenetic disorders, particularly DSM-IV impulse controldisorders such as intermittent explosive disorder, kleptomania,pyromania, pathologic gambling, trichotillomania, and other impulsecontrol disorders such as compulsive buying and problematic Internetuse. In a preferred embodiment, the subject invention provides methodsfor treating or controlling symptoms associated with ADHD or PWScomprising the administration of therapeutically effective amounts ofcompositions containing compounds of the formulas I-V. In anotherembodiment, the subject invention provides for methods of promotingwound healing comprising the administration of a therapeuticallyeffective amount of a composition comprising the compounds of formulasI-V. Compositions are administered to a wound site via a salve,ointment, or as a component of a bandage or bioadhesive applied to thesite of injury. The invention also provides therapeutically effectivecompositions comprising one or more of the compounds of formulas I-V.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication, withcolor drawing(s), will be provided by the Office upon request andpayment of the necessary fee.

FIGS. 1, 3, 5, and 7 depict the efficiency ratios of patients treatedwith topiramate as measured by the Delay Task of the Gordon Diagnostic.

FIGS. 2, 4, 6, and 8 depict the total correct responses of patientstreated with topiramate as measured by the Vigilance Task of the GordonDiagnostic.

FIGS. 9A-D and 10A-C depict the progression of wound healing in patientstreated with topiramate.

FIGS. 11A-B: Photographs of improvement in wound healing for Ms. A ontopiramate (75 mg/day) at week 4 (FIG. 11A) and 150 mg/day topiramate atweek 8 (FIG. 11B).

FIGS. 12A-B: Photographs of improvement for Mr. B. Mr. B. on 25 mg/daytopiramate (FIG. 12A), Week 1; Mr. B. on 200 mg/day topiramate (FIG.12B), Week 8.

FIGS. 13A-B: Photographs of primary SIB lesions. Ms. C. (right breast),baseline (FIG. 13A); Ms. C. on 175 mg/day (right breast), Week 8 (FIG.13B).

FIG. 14: Number of ulcerated SIB lesions for Ms. C. as documented bygroup home staff utilizing systematic full body surveys (* denoteslesions smaller than previous lesions and appearing to result afterinsect bites).

FIGS. 15A-B: Photographic record of Ms. A hair loss at start oftreatment (FIG. 15A) and during treatment (FIG. 15B).

FIG. 16 illustrates the reported reduction in the urge of Ms. A to pullhair.

FIG. 17 represents the improvement in impulse control for Ms. A duringtreatment using the Gordon Diagnostic System.

FIG. 18 illustrates that Ms. A suffered no significant change incognitive ability during treatment.

DETAILED DISCLOSURE OF THE INVENTION

The subject invention provides methods and compositions for thetreatment of neurogenetic disorders, particularly DSM-IV impulse controldisorders such as intermittent explosive disorder, kleptomania,pyromania, pathologic gambling, trichotillomania, and other impulsecontrol disorders such as compulsive buying and problematic Internetuse. In a preferred embodiment, an individual is treated in methodscomprising the administration of therapeutically effective amounts ofcompositions comprising compounds selected from the group consisting offormulas I-V. In one embodiment, therapeutically effective amounts oftopiramate are administered to individuals topically or orally. Inanother embodiment, compositions comprising one or more of the compoundsdisclosed in formulas I-V are administered for the control or treatmentneurogenetic disorders. In preferred embodiments the neurogeneticdisorders include PWS and ADHD.

Thus, the subject invention provides methods and compositions for thetreatment or control of ADHD or PWS. In one embodiment, the subjectinvention provides methods for controlling symptoms associated with ADHDor PWS comprising the administration of therapeutically effectiveamounts of compositions containing compounds of the formulas I-V. Oneembodiment of the invention provides therapeutically effectivecompositions comprising one or more of the compounds of formulas I-V andacceptable carriers.

In another embodiment, the subject invention provides methods ofpromoting wound healing comprising the administration of atherapeutically effective amount of a composition comprising thecompounds of formulas I-V to an individual having a wound. In oneembodiment, compositions are topically administered to a wound. Thecompositions may take the form of a salve, ointment, or aerosol appliedto the site of injury. Alternatively, the compositions may beadministered to the wound site as a component of a bandage ortransdermal patch. In these instances, the compositions may be anintegral component of the bandage or transdermal patch and are therebyapplied to the wound site. In another embodiment, therapeuticallyeffective amounts of the compounds comprising formulas I-V areincorporated into bioadhesive compositions useful in wound closure. Inyet another embodiment, therapeutically effective amounts compositionscomprising the compounds of formulas I-V are administered orally.

As the subject invention provides methods of promoting wound healing orcontrolling impulsive behavior in an individual, the subject inventionprovides methods having both human and veterinary utility. The term“individual” includes animals of avian, mammalian, or reptilian origin.Mammalian species which benefit from the disclosed methods include, andare not limited to, apes, chimpanzees, orangutans, humans, monkeys;domesticated animals (pets) such as dogs, cats, guinea pigs, hamsters,Vietnamese pot-bellied pigs, rabbits, and ferrets; domesticated farmanimals such as cows, buffalo, bison, horses, donkey, swine, sheep, andgoats; exotic animals typically found in zoos, such as bear, lions,tigers, panthers, elephants, hippopotamus, rhinoceros, giraffes,antelopes, sloth, gazelles, zebras, wildebeests, prairie dogs, koalabears, kangaroo, opossums, raccoons, pandas, giant pandas, hyena, seals,sea lions, and elephant seals. Reptiles include, and are not limited to,alligators, crocodiles, turtles, tortoises, snakes, iguanas, and/orother lizards. Avian species include, and are not limited to, chickens,turkeys, pigeons, quail, parrots, macaws, dove, Guinea hens, lovebirds,parakeets, flamingos, eagles, hawks, falcons, condor, ostriches,peacocks, ducks, and swans. Therefore, the subject invention providesmethods of controlling the impulse of an individual to scratch, pick,lick, or otherwise cause self-injury by repeated mechanical irritationof an injured area.

Bandages and wound dressings incorporating materials to promote woundhealing are well known in the art (see, for example, U.S. Pat. Nos.6,143,037; 6,142,982; 6,136,341; 6,132,759; 6,124,273; 6,096,709;6,093,388; 6,087,549; 6,051,249; 6,033,684; 6,025,150; 6,022,556;5,998,692; 5,989,577; 5,981,606; 5,977,428; RE36,370; 5,972,332;5,968,001; 5,960,795; 5,955,430; 5,914,125; 5,902,600; 5,897,516;5,876,743; 5,874,479; 5,863,938; 5,856,364; 5,856,245; 5,834,432;5,807,341; 5,807,300; 5,804,213; 5,780,048; 5,759,570; 5,735,812;5,716,935; 5,716,337; 5,713,842; 5,707,647; 5,705,477; 5,692,302;5,685,834; 5,674,912; 5,667,501; 5,663,208; 5,662,924; 5,662,904;5,658,957; 5,658,956; 5,652,274; 5,648,380; 5,646,190; 5,641,814;5,633,285; 5,632,727; 5,629,292; 5,614,561; 5,610,148; 5,603,946;5,602,183; 5,578,022; 5,571,521; 5,525,335; 5,522,794; 5,520,926;5,519,020; 5,512,291; 5,512,041; 5,507,775; 5,578,310, each of which isincorporated by reference in its entirety).

Bioadhesives incorporating materials to promote wound healing are wellknown in the art (see, for example, U.S. Pat. Nos. 5,981,606; 5,874,479;5,863,938; 5,856,364; 5,692,302; 5,674,912; 5,663,208; 5,658,957;5,658,956; 5,652,274; 5,648,380; 5,646,190; 5,641,814; 5,633,285;5,631,019; 5,614,561; 5,602,183; 5,578,310, each of which isincorporated by reference in its entirety).

Compounds of formulas I-V are anti-epileptic compounds, which are highlyeffective anti-convulsants. The compounds useful in the practice of theinstant invention include the individual isomers, analogs, and homologsof the disclosed anti-convulsant compounds. Racemic mixtures, as well asthe isolated enantiomeric forms, of the compounds can also be used inthe practice of the subject invention.

In addition, the compounds useful for the practice of the subjectinvention include pharmaceutically acceptable salts, for example; alkalimetal salts, such as sodium or potassium, ammonium salts, dialkyammoniumsalts, trialkylammonium salts, tetraalkylammonium salts, andtromethamine salts. Hydrates and other solvates of the compounds arealso included within the scope of the compounds useful in the practiceof this invention.

One such compound is taught and disclosed in U.S. Pat. No. 4,513,006,hereby incorporated by reference in its entirety.2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate, knownas topiramate, has been demonstrated in clinical trials of humanepilepsy to be effective as adjunctive therapy or as monotherapy intreating simple and complex partial seizures and secondarily generalizedseizures. Other useful compounds include those described by formula I,including (tetrahydro-2H-pyran-2-yl)methane sulfamate, and2,3:4,5-bis-O-(1-methylethylidene) -β-D-fructopyranose methylsulfamate

wherein

X₁ is CH₂ or oxygen;

R₁ is hydrogen or alkyl; and

R₂, R₃, R₄, and R₅ are independently hydrogen or lower alkyl and, whenX₁ is CH₂, R₄, and R₅ may be alkene groups joined to form a benzene ringand, when X₁ is oxygen, R₂ and R₃ and/or R₄ and R₅ together may be amethylenedioxy group of the following formula:

wherein R₆ and R₇ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.

For compounds of formula I, R₁ may be hydrogen or an alkyl of about 1 to4 carbons, such as methyl, ethyl, and isopropyl. Alkyl includes straightand branched chain alkyl. For compounds of formula I, Alkyl groups forR₂, R₃, R₄, R₅, R₆, and R₇ are of about 1 to 3 carbons and includemethyl, ethyl, isopropyl and N-propyl.

When X₁ is CH₂, R₄ and R₅ may combine to form a benzene ring fused tothe 6-membered X₁-containing ring, i.e., R₄ and R₅ are defined by thealkatrienyl group ═CH—CH═CH—CH═.

In one embodiment, X₁ is oxygen and both R₂ and R₃ and R₄ and R₅together are methylenedioxy groups of the formula wherein R₆ and R₇ areboth hydrogen, both alkyl or combine to form a spiro cyclopentyl orcyclohexyl ring, in particularly where R₆ and R₇ are both alkyl such asmethyl. In another embodiment, X₁ is CH₂ and R₄ and R₅ are joined toform a benzene ring. Another embodiment provides compounds of formula(I) wherein both R₂ and R₃ are hydrogen.

Other compounds (formulas II-VI) and compositions useful in the practiceof the subject invention may be found in the teachings of U.S. Pat. Nos.5,384,327, 5,498,629, 5,654,461, 5,892,088, and 6,071,537, each of whichis incorporated by reference in their entireties.

These compounds include those provided by the structure:

wherein R₆ and R₇ may be the same or different and are selected from anyof hydrogen or C₁ to C₄ alkyl. In one embodiment, R₆ and R₇ are eachhydrogen.

R₈ and R₉ may be the same or different and are selected from any ofhydrogen or C₁ to C₄ alkyl. In one embodiment, R₈ and R₉ are each C₁ toC₄ alkyl.

R₁₀ and R₁₁ may be the same or different and are selected from any ofazido, halogen, hydroxyl, sulfamoyl (H₂NSO₂O), C₁ to C₄ alkoxy, C₁ to C₄alkyl thiocarbonate (RSC(O)O), C₁ to C₄ alkyl carbonate (ROC(O)O), or C₁to C₄ alkyl carboxylate (RC(O)O), wherein R is C₁ to C₄ alkyl. In oneembodiment, R₁₀ and R₁₁ are selected from any of C₁-C₄ alkylthiocarbonate, halogen or hydroxyl.

For compounds of formula II, the terms alkyl and alkoxy include straightand branched chains. For example, alkyl radicals include methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, and t-butyl. Halogen includesbromine, chlorine, fluoride and iodine.

Preferred compounds of the formula (II) are those wherein the pyran ringis in the L-sorbopyranose absolute configuration. Particularly preferredcompounds of formula (II) are those wherein the pyran ring is in theL-sorbopyranose absolute configuration, R₆ and R₇ are each hydrogen, R₈and R₉ are each methyl; R₁₀ is methyl thiocarbonate (CH₃SC(O)O) and R₁₁is halogen; or R₁₀ and R₁₁ are both halogen; or R₁₀ is hydroxyl and R₁₁is halogen. Particularly preferred halogens include bromine, chlorine,and iodine.

Specific examples of compounds of formula (II) are: (1)5-deoxy-5-iodo-2,3-O-(1-methylethylidene)-4-[methylthiocarbonyl)]-α-L-sorbopyranose sulfamate, (i.e., where thecompound is in the L-sorbopyranose absolute configuration, R₆ and R₇ arehydrogen, R₈ and R₉ are methyl, R₁₀ is CH₃SC(O)O, and R₁₁ is iodine);(2) 4,5-dibromo-4,5-dideoxy-2,3-O-(1-methylethylidene)-α-L-sorbopyranose sulfamate, (i.e., where the compound is in theL-sorbopyranose absolute configuration, R₆ and R₇ are hydrogen, R₈ andR₉ are methyl, R₁₀ and R₁₁ are bromine); and (3)5-chloro-5-deoxy-2,3-O-(1-methylethylidene)-α-L-sorbopyranose sulfamate,(i.e., where the compound is in the L-sorbopyranose absoluteconfiguration, R₆ and R₇ are hydrogen, R₈ and R₉ are methyl, R₁₀ ishydroxyl, and R₁₁ is chlorine).

Another compound useful in the practice of the invention is described inFormula III:

wherein R₁₂ and R₁₃ are the same or different and are selected from anyof hydrogen, alkyl (C₁ to C₆), cycloalkyl (C₃-C₇), allyl, or benzyl. Inone embodiment, R₁₂ and R₁₃ are each hydrogen. R₁₄ and R₁₅ are the sameor different and selected from hydrogen or lower alkyl.

X₂ may be chosen from carbon (C) or sulfur (S), with the stipulationthat when X₂ is carbon, R₁₆ and R₁₇ are the same or different and areselected from hydrogen or lower alkyl, whereas when X₂ is sulfur one ofR₁₆ and R₁₇ is oxygen and the other is a lone pair of electrons or bothR₁₆ and R₁₇ are oxygen.

For compounds of formula III, the term alkyl includes straight andbranched chains. For example, alkyl radicals include methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, and t-butyl.

Particularly preferred compounds of formula III are: (1)(1R,2R,3S,4S)-(1,2:3,4-di-O-methylethylidenecyclohexan-1,2,3,4-tetraol-r-yl)methyl sulfamate, (i.e., where R₁₂ and R₁₃ arehydrogen, R₁₄, R₁₅, R₁₆, and R₁₇ are methyl and X₂ is carbon); (2)(1R,2S,3S,4S)-(3,4-O-methylethylidene-1,2-O-sulfonyl-cyclohexan-1,2,3,4-tetraol-4-yl) methyl sulfamate,(i.e., where R₁₂ and R₁₃ are hydrogen, R₁₄ and R₁₅ are methyl, R₁₆ isoxygen and R₁₇ is an electron pair and X₂ is sulfur); and (3)(1R,2S,3S,4S)-(3,4-O-methylethylidene-1,2-O-sulfonyl-cyclohexan-1,2,3,4-tetraol-4-yl)methylsulfamate, (i.e., where R₁₂ and R₁₃ are hydrogen, R₁₄ and R₁₅ aremethyl, R₁₆ and R₁₇ are both oxygen and X₂ is sulfur).

Another compound useful in the subject invention is

Other compounds useful in the practice of the invention include those ofFormula V

wherein, AR is represented by the following formulas:

Y is selected from the group consisting of halogens such as F, Cl, Brand I, or trifluoromethyl and alkyl groups containing 1 to 3 carbonatoms when Y alone is attached to the benzene ring; when X₃, which maybe S or O, is present, Y is selected from the group consisting oftrifluoromethyl and alkyl groups containing 1 to 3 carbon atoms.R₁₈,R₁₉, R₂₀, and R₂₁, may be identical or different and are selected fromthe group consisting of hydrogen, linear or branched alkyl groupscontaining 1 to 16 carbon atoms, cyclic alkyl groups containing 3 to 16carbon atoms and aryl groups containing 6 to 8 carbon atoms, and NR₁₈R₁₉and NR₂₀R₂₁, identical or different, each may form a 3 to 7-memberedaliphatic cyclic compound together with another nitrogen atom or oxygenatom.

Compositions useful in the practice of this invention comprise one ormore of the compounds of formulas I-V admixed with a pharmaceuticalcarrier. The compositions may be made according to conventionalpharmaceutical compounding techniques. Thus, the carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., injection, oral, suppository, topical, orparenteral.

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be sugarcoated or enteric coated by standard techniques. Suppositories may beprepared, in which case cocoa butter could be used as the carrier.

For parenterals, the carrier will usually comprise sterile water, thoughother ingredients, for example, for purposes such as aiding solubilityor for preservation, may be included. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed.

Other compositions useful in the practice of the subject inventioninclude salves, cosmetics, ointments, and the like. Such compositionsmay be topically applied to a site or incorporated into articles ofmanufacture including, but not limited to, bandages, adhesive strips forthe covering of wounds (e.g., BANDAID brand adhesive strips), ortransdermal patches. Carriers such as cocoa butter, viscous polyethyleneglycols, hydrogenated oils, and such mixtures can be emulsified ifdesired.

Compounds of the subject invention may also be incorporated intocosmetics. Additional materials and substances suitable as carriers forthe compounds of formulas I-V are described in the InternationalCosmetic Ingredient Dictionary and Handbook, 8^(th) Edition (TheCosmetic, Toiletry, and Fragrance Association (CTFA), 2000), herebyincorporated by reference in its entirety.

Where the pharmaceutical compositions are aerosols, the activeingredients can be packaged in pressurized aerosol containers with apropellant, e.g., carbon dioxide, nitrogen, propane, etc. with the usualadjuvants such as cosolvents, wetting agents, etc.

In accordance with the invention, pharmaceutical compositions comprise,as an inactive ingredient, an effective amount of one or more non-toxic,pharmaceutically acceptable ingredient(s). Examples of such ingredientsfor use in the compositions include ethanol, dimethyl sulfoxide,glycerol, silica, alumina, starch, calcium carbonate, talc, flour, andequivalent non-toxic carriers and diluents.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder injection, teaspoonful, suppository,bandage, and the like, from about 0.1 to about 400 mg of the activeingredient. In a preferred embodiment, the compositions comprise about10 mg to 200 mg per dosage unit. In an even more preferred embodiment,the compositions contain comprise about 20 mg to about 100 mg of activeingredient. In another embodiment, the compositions comprise about 25 mgof active ingredient per unit dose.

Topiramate is currently available for oral administration in roundtablets containing 25 mg, 100 mg or 200 mg of active agent. The tabletscontain the following inactive ingredients: lactose hydrous,pregelatinized starch, microcrystalline cellulose, sodium starchglycolate, magnesium stearate, purified water, carnauba wax,hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol,synthetic iron oxide, and polysorbate 80.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims. All publications andpatents cited herein are hereby incorporated by reference in theirentireties.

EXAMPLE 1 Effects of topiramate on impulsivity and cognitive functioning

There are no reports of topiramate being utilized in PWS for anybehavior. Measurements of attention, concentration, and impulsivity wereassessed by the Delay and Vigilance tasks of the Gordon DiagnosticSystem (GDS; Gordon, M.; McClure, F. D.; & Aylward, G. P. (1996) GordonDiagnostic System, Interpretive Guide (Third Edition); Dewitt, N.Y.:Gordon Systems, Inc.), a mechanized evaluator of cognitive functions,including attention and concentration. The GDS was originally developed,and most commonly used, to measure aspects ofAttention-Deficit/Hyperactivity Disorder (ADHD) (previously calledAttention-Deficit Disorder). One of the important components of theVigilance test is the ability of an individual to have sustainedattention, and the Delay task in part measures the subjects' ability toconcentrate and focus on hitting a button at appropriate time intervalsand delay impulsive behavioral responses.

The Delay Task requires that the subject inhibit responding (pressing abutton and then refraining from pressing the button again for at least 6seconds) in order to earn points. The Delay Task measures the subject'sability to suppress and delay impulsive behavioral responses. Whilefocusing and sustaining attention usually facilitate Delay Taskperformance, the Delay Task maximally draws on a subject's ability toinhibit impulsive responses. The Delay Task's total efficiency ratio(EF) is considered the best indicator (score ranges from 0 to 1) of thelevel of impulsivity with the lower the score (such as less than 0.5)indicating higher impulsivity and poor self-control. The Vigilance Taskmeasures the subject's ability to focus attention on a task and tomaintain this attention over a period of time without reinforcement. Thecorrect responses (CR) of the Vigilance Task measures the level ofalertness and is a measure of the subjects attentional processes.

JAS-002 (patient Number 2) had a baseline total efficiency ratio (ER) of0.02, approximately 8 standard deviations below the normal range andwell below the first percentile in regards to the Delay task. This fallsmarkedly within the range of an “abnormal” performance as stated in therating score manual provided by the manufacturer of the GDS. At visit 4,approximately 1 month after starting medication (at a dose of 100mg/day), JAS-002 demonstrated dramatic improvement in ER (a value of0.98), well within the normal range of performance. At 2 months (at adose of 175 mg/day), JAS-002 continued with improvements in ER (a valueof 0.85), within the normal range of performance. Attention as evaluatedby the Vigilance Task for JAS-002 showed essentially no change for CRfrom 39 at baseline to 38 (at a dose of 175 mg/day) at 2 months.

For patient Number 1 (MJG-001), a significant improvement has beennoted. At baseline, MJG-001's ER for the Delay Task was at a value of0.06 (approximately 7 standard deviations below the average ER)demonstrating a severe impairment of impulsivity. However, at the secondtesting session, MJG-001 showed moderate improvement with a Delay TaskER of 0.24. At visit 5, approximately 1.5 months after startingmedication (at a dose of 75 mg/day), MJG-001 demonstrated a substantialimprovement with an ER value of 0.46 and two weeks later (at a dose of125 mg/day) had an ER value of 0.70. At 2 months after startingmedication (at a dose of 150 mg/day), MJG-001 demonstrated a substantialimprovement with an ER value of 0.50. The Vigilance Task for MJG-001showed some variability up and down during the study and, afterapproximately 2 months, showed a mild decrease of CR from 43 to 41 (at adose of 150 mg/day).

Patient Number 3 (GFV-003) has also shown a severe deficit inimpulsivity and focusing; baseline ER was 0.02 (a value 8 standarddeviations below the normal range). At visit 1, after one week at a lowdose of topiramate (25 mg/day), GFV-003 had improved to an 0.09 ER andby week 4 (at a dose of 100 mg/day) to an ER of 0.19, and by 2 months(at a dose of 200 mg/day) the ER was at 0.10. The Vigilance Task forGFV-003 showed variability on topiramate and by the end of two monthswas essentially unchanged with a CR decreasing from 16 at baseline to 15at 2 months.

Patient #4 (MCK-004) also showed abnormal performance on the Delay task(ER of 0.35). Within 1 week on low dose topiramate (25 mg/day) MCK-004had improved to an ER of 0.51, by the 2^(nd) week on 50 mg/daytopiramate, the ER was 0.76, and continued improvement by the 3^(rd)week on 75 mg/day with an ER of 0.65 and by two months at a dose of 150mg/day, her ER continued to be improved at 0.64. The Vigilance Task forMCK-004 shows mild decrease from baseline CR of 38 to 34 (by the 8^(th)week on 150 mg/day).

Thus, the use of topiramate for impulsivity, without negative effects onattention and concentration, is both novel and clinically applicable.Disorders with impulsivity and deficits in attention and concentrationare difficult to manage for both the patient and their caregiver,especially in cases of dementia. Impulsivity and lack of concentrationcan severely handicap day-to-day functioning in all age groups affectedby these disorders. There are no reports in the literature of topiramatespecifically used to treat impulsivity and/or deficits in attention andconcentration.

EXAMPLE 2 Effect of topiramate on pathologic skin picking (PSP)

There are no reports of topiramate being utilized in PWS for anybehavior. Patient #3 (GFV-003) also has pathologic skin picking (PSP) inaddition to food seeking behavior. Patient #3 has a chronic large lesionon his lower left arm. Within one week of topiramate (25 mg/day), he haddecreased skin picking and showed healing of this lesion on his leftarm. By the 4^(th) week on topiramate (at 100 mg/day), the lesion on hislower left arm had completely healed over. The progression of woundhealing is provided in FIGS. 9A-D and 12A-B.

Patient #1 (MJG-001) has pathologic skin picking (PSP) in addition tofood seeking behavior. Unexpectedly and serendipitously, it was observedthat several large lesions (where she skin picks) on her right arm,legs, and lips were clearing up quickly (within 5 days) after topiramatewas initiated at 25 mg/day. Furthermore, the patient has continued to dowell in terms of skin clearing. For example, a large lesion on her rightarm completely healed over after about 2 months on topiramate (at a doseof 125 mg/day). The patient lives in a group home and workers there, aswell as her mother, have also commented to us that her skin picking/skinhas overall improved. The progression of wound healing is provided inFIGS. 10A-C and 11A-B.

The use of topiramate for PSP and related disorders is also novel andclinically applicable. There are no FDA approved pharmacologicaltreatments for pathologic skin picking (also referred to as neuroticexcoriation, repetitive skin picking, compulsive skin picking, anddermatotillomania) and possible related obsessive-compulsive spectrumdisorders (i.e., repetitive self-mutilation (RSM), oncophagia,rhinotillxomania, trichotillomania) (Goldsmith, T. D.; Shapira, N. A.;Phillips, K. A.; et al., “Obsessive compulsive spectrum disorders”; in:Swinson, R. P.; Antony, M. M.; Rachman, S.; Richter, M. A. (Eds).,Obsessive-Compulsive Disorder: Theory, Research, and Treatment, GuilfordPublications, New York, pp.397-425 (1998)).

EXAMPLE 3 Effects of Topiramate on patients with Prader-Willi Syndrome

In an 8-week, open-label, flexible-dose (maximum 350 mg/day) study toevaluate the efficacy and safety of topiramate in PWS adults, weeklyevaluations were performed that included scales for stereotypicalbehavior (Stereotypy Checklist, Y-BOCS checklist), aberrant behavior(Aberrant Behavior Scale {ABS}, Severity of Symptoms Scale, Self-Injuryand Self-Restraint Checklist) and cognitive functioning (GordonDiagnostic, Controlled Oral Word Association Test, Semantic Namingtest). Subject safety measures were also performed (e.g., monitoringblood pressure). Appetite was assessed for one hour at four time pointsduring the trial. Measurements were made by investigator observation ofthe subject with free access to low calorie food and a visual analoguescale before and after observation.

Eight subjects (19-36 years of age; 4 males and 4 females) entered thetrial and six have completed the treatment regimen. A mean weight lossof 0.3 pounds was observed over the course of the study. Appetite testsshow a mean increase of 255.8 calories/hour; however, a dramaticreduction in self-injurious behavior was also observed (e.g., skinpicking). Five subjects have continued long-term on topiramate for atleast 6 months (mean of 8.2±1.5 months) and, in these subjects, therehas been mean 4.9 lb±4.0 lb weight loss. Behavior evaluations have showna reduction in aberrant behaviors (such as irritability andnoncompliance [Mean ABS at baseline of 8.5±7.2 and mean ABS at week 8 of5.3±5.1, *Z=−2.0, df=1, P=0.042 {Wilcoxon signed-ranks test}]) andself-injury in all four subjects exhibiting these behaviors. Healing ofskin lesions was also observed. Open-label administration of topiramatehas been shown to improve behavior and decrease self-injury in PWSsubjects. Longer treatment lengths appear to result in steady weightdecrease.

EXAMPLE 4 Effects of Topiramate on Prader-Willi Syndrome

In the above study was performed to assess the effects of topiramate onPWS. All subjects provided written informed consent for topiramatetreatment and were between 18 and 65 years of age. Criteria forexclusion included: clinically significant suicidality or homicidality;current or recent (within 6 months of the start of topiramate) DSM-IVdiagnosis of substance abuse or dependence; a clinically unstabledisease that could interfere with treatment or assessment of PWS;treatment with any drug that might interact adversely with topiramate;and personal or family history of nephrolithiasis. Women of childbearingpotential who were not taking adequate contraceptive measures were notincluded. Screening measures included a physical examination,psychiatric background, medication history, blood draw for laboratoryassessment (CBC, SMA-12, urinalysis, and a B-hCG for women ofchildbearing potential), and the Structured Clinical Interview forDSM-IV, Patient Edition (SCID-P). Weekly assessments of weight loss,participant functioning, and safety measures including blood pressureand pulse were taken by the investigators at each visit. Participantsare residents of group homes operated by the Association of RetardedCitizens, Alachua County, Florida (ARC). These homes are monitored,thereby allowing recording of participants' behavioral and psychiatricmanifestations as well as their medication management. Participantsbegan pharmacotherapy with topiramate at 25 mg of drug given in theevening for 7 days. After 14 days, their daily dose could be increasedin increments of up to 50 mg/week for the next 6 weeks.

Case 1: Ms. A. is a 19 year-old female who through DNA methylationtesting was positive for PWS and shown to have a chromosomal deletionthrough FISH and DNA polymorphism analyses. Ms. A. has a history ofhoarding and severe skin picking dating to childhood. Currentconcomitant psychiatric medications include fluoxetine 60 mg/day andnaltrexone 50 mg/day. Psychiatric intervention dated back to 1992 whenthe subject began therapy with clomipramine and fenfluramine, both ofwhich were unsuccessful in managing her behavior and weight problem.

Initial side effects (of topiramate) experienced included mild sedation,word-finding difficulties, and unrelated lower back pain that resolvedby Week 8. Ms. A's weight remained stable with a baseline of 129.5 lbsand weight of 128.5 lbs at Week 8. Ms. A had a long-standing primarylesion on her right forearm that measured approximately 4 cm by 1 cm andulcerated at baseline. She experienced a reduction in skin picking withimprovement to the lesions on her face, arm, and legs noted by Week 4(75 mg/day). To better follow the improvement in her skin, aphotographic record of Ms. A's lesion on her forearm was begundemonstrating healing of this lesion by Week 8 of topiramate (150mg/day). See FIGS. 10A-C and 11A-B.

Case 2: Mr. B. is a 29 year-old male confirmed to be a chromosomaldeletion as described above. He has a history of severe food seeking andskin picking dating to childhood. Mr. B does not have a history oftaking psychotropic medications and had declined a previousrecommendation to take fluoxetine. Initial healing of his primary lesion(a round 1.5 cm diameter ulcerated lesion) was noted within one week ofinitiating topiramate treatment (25 mg/day) at which point photographicrecords were started. Mr. B also experienced some increased irritabilitywhen topiramate was initiated. Irritability returned towards baseline byWeek 8. Mr. B also experienced a decrease in his weight from 180.0 lbsat baseline to 176.8 lbs at Week 8. By Week 8 of topiramate (200mg/day), Mr. B. had experienced remission of his self-injurious behavior(SIB) with resultant healing and complete unulceration of his primarylesion (FIGS. 9A-D and 12A-B).

Case 3: Ms. C. is a 32 year-old female confirmed to be a chromosomaldeletion. Concomitant psychotropic medications include fluoxetine 20mg/day. She has a history of food seeking and skin picking dating tochildhood. Due to her employment, Ms. C. picks in multiple concealedlocations (e.g., her chest, breasts, and the top of her legs). Becauseof her secrecy regarding SIB, the staff members of her group home dailyperform full body surveys. As a result of previous experience with Ms. Aand Mr. B, photographic records of her lesions were started prior toinitiation of topiramate (FIG. 13).

After beginning topiramate, an attenuation of SIB behavior and number ofulcerated lesions (FIG. 14) was noted within 1 week (25 mg/day) byphotographs and by 2 weeks (50 mg/day) by her group home staff. Sideeffects included word-finding difficulty, mild confusion, sedation, andsome mild tingling in her left heel. All side effects resolved by Week5. On topiramate, Ms. C experienced an increased weight from 150 lbs atbaseline to 154.5 lbs at Week 8. At Week 8, Ms. C. had continuedattenuation of skin picking on a dose of 175 mg/day (FIGS. 14 and 15).During participation, Ms. C. experienced a period of three weeks whereshe was without any SIB. However, reportedly as result of her picking atseveral insect bites, small ulcerated lesions appeared on her forearmand lower legs in Weeks 7 and 8.

These three cases further illustrate the beneficial effects of theanti-epileptic drug topiramate. Topiramate is able to attenuateself-injurious behavior in a patient population where SIB is common anddifficult to manage and treat. All three subjects have longstandinghistories of self-injury, and two subjects (Ms. A. and C.) had failedprevious psychotropic medication interventions. Furthermore, all threePWS subjects have chosen to continue on topiramate after the 8-weektrial (8 months for Ms. A., 7 months for Mr. B., and 4 months for Ms.C.) with continued improvement in self-injury. Improvement inself-injury was noted by both investigators and in systematic bodyevaluations by the group home in one subject (Ms. C.). Additionally,while individuals with PWS often pick surreptitiously and pick even whenthey describe having no urges, all three subjects reported decreasedurges to pick while on topiramate.

In terms of an objective measurement of impulsivity, subjects were alsofollowed by the Delay Task of the computerized Gordon Diagnostic System(Gordon et al., 1996). The Delay Task measures a subject's ability tosuppress and delay impulsive behavioral responses (Gordon et al., 1996).All three subjects demonstrated improvement in the Delay Task while ontopiramate.

EXAMPLE 5 Effects of Topiramate on Impulsive Disorders in Mammals

Canine acral lick dermatitis (ALD), also known as lick granuloma, acralpruritic nodule, and neurodermatitis, is a common self-inflicted skindisorder in dogs in which localized alopecia and epidermal hyperplasiaand fibrosis are caused by continued licking, biting, and/or scratchingone or more areas usually near the carpus or hock. When severe, thelicking of the paws or flank causes significant local trauma and, inextreme cases, may require surgery and steroids. Occasionally, theanimal must be put to death because of chronic ulceration orosteomyelitis. The etiology of ALD is unknown, although, commonly, it isconsidered to be psychogenic in origin secondary to boredom, loneliness,or confinement. It can also be provoked by local irritation. Certainlarge breeds appear to be more susceptible, such as German Shepherds,Labrador Retrievers, and Great Danes. The repetitive self-licking,chewing, or scratching creates areas of hair loss and the production oflesions which may range in size from several centimeters to the entiresurface of the limb. This stereotypic behavior prevents the lesions fromhealing and may cause discomfort, pain and, in severe cases, may provecrippling.

Twenty dogs will be recruited from the Veterinary Animal TeachingHospital. Other causes of licking will be ruled out by examining thedogs' clinical history, typical lesion appearance, and past history oftreatment response. Dogs must exhibit chronic licking of 6 months ormore that has caused an observable lesion(s). Reasons for exclusion fromthe study include: dogs undergoing concurrent treatment for ALD, dogsweighing <5 kg, dogs that have not been neutered or spayed,nephrolithiasis, and a significant acute or chronic confounding disease.Once the referring veterinarian has consented to the dogs' involvement,letters inviting participation in the study will be sent out to theowners of appropriate candidates. An informed consent documents willalso be obtained.

A double-blind placebo-controlled trial of 8 weeks duration (6 weektreatment and 2 week taper) will be conducted. One-half of the dogsreceive placebo. The dogs will start at 2 mg/kg in a split dose (1 mg/kgtwice a day) for the first two weeks. The dose will be increased 2 mg/kga week as tolerated for the next four weeks. Thus, the maximum dosagewill not exceed 10 mg/kg. This dosage strategy is based upon the targetdose for seizures, which is 5 to 10 mg/kg in split doses.

Topiramate or placebo will be administered via gelatin capsules oncedaily (5 minutes before feeding). Owners will be instructed to avoidfeeding dogs anything in addition to their regular diet. In addition toadhering to the dogs' routine (e.g., food, exercise, and training),owners will also be asked to maintain environmental conditions for theduration of the study.

A video camera will record the dogs' behavior for 1 hour each week forthe 6 weeks of the trial. The primary behavior of interest isself-licking or self-chewing of the granulomatous lesion. The measure oftime the dogs are involved in licking or chewing will be computerized.The evaluator will press the designated key when the dog's tongue orlips first makes contact with the lesion, and at the end of a continuousbout of licking or chewing when the dog lifts its head from the lesionand transfers its attention elsewhere.

In addition to videotaping, the owners will rate their dogs' lickingbehavior on a 10-point scale, with 10 being the worst ever observed and0 indicating a complete absence of excess licking (Acral Lick DermatitisSeverity Scale). Investigators will also rate the dogs' behavior using asimilar scale. Finally, photographs of the lesions will be taken weekly.Additionally, at baseline, a checklist for phobias will be done with theowners and the list will be reviewed each week using clinical globalimpression scales to rate phobias.

A 2-week taper period will follow the 6-week treatment period. Duringweek 7, study medication will be reduced by approximately 25% for 3days. On day 4, the dosage will be reduced by another 25%. On day 11 theremaining dose will be reduced in half again and on day 13 all studymedication will be stopped. The dogs' last visit will be day 14 of thetaper period.

For each of the efficacy measures, a listing of each patient's score ateach study week during treatment will be generated. The evaluation ofchange in efficacy measurements will be carried out using standardanalysis of variance techniques. All statistical tests will be two-sidedif not otherwise specified. A test will be said to be significant ifp<0.05. Analyses will be preformed using the “intent-to-treat”population consisting of all dogs randomized into the trial that take atleast one capsule of study medication and had at least one post-baselineevaluation. The primary efficacy variable will be the number ofself-injurious behaviors observed by video camera during weekly visits.A dog's self injury duration (in min/hr) is measured at the baseline andsix weeks after treatment. The improvement score is the percentage ofreduction (in ratio), i.e.,improvement=(baseline−posttreatment)/baseline.

EXAMPLE 6 Effects of topiramate on trichotillomania

Topiramate was used as an adjunct therapy in a 38 year-old female with a9-year history of trichotillomania. She was on a stable dose combinationof fluvoxamine and clomipramine. While the fluvoxamine/clomipraminecombination was therapeutic for 3 years, 6 months ago Ms. A experiencedan increase in hair pulling predominately on the left side of her head.The investigators have made photographic records of Ms. A's hair loss(FIGS. 15A-B) and she has been evaluated psychometrically for impulsecontrol. Ms. A was started on a 25 mg dose of topiramate at night andwas gradually titrated in increments of 25 mg to 150 mg at night.Preliminary results suggest the addition of topiramate to thiscombination therapy effective for trichotillomania.

Before topiramate was initiated, clomipramine blood levels were asfollows: clomipramine=354 ng/ml, DM clomipramine=118 ng/ml, andclomipramine+DM clomipramine=472 ng/ml. Following the addition oftopiramate Ms. A reported a lessening of the urges to pull her hairstarting at a relatively low dose (approximately 50 mg/ day). Ms. Areported a significant reduction in the urge to pull by 3 weeksfollowing the addition of topiramate and this improvement has beenmaintained for 14 weeks (FIG. 16). Although patient described decreasedurges to pull hair, her re-growth was minimal. Subsequent laboratoryassessments when patient was on 150 mg of topiramate, 100 mg ofclomipramine and 50 mg of fluvoxamine showed that although the ratio ofparent to metabolite were the same as before topiramate (0.69), bothmeasurements were elevated: clomipramine=514 ng/ml, DM clomipramine 181ng/ml, clomipramine+DM clomipramine=695 ng/ml.

After initial success with topiramate augmentation, the patient iscurrently being weaned off clomipramine and is currently on 25 mg/dayfrom 100 mg/day without any increase in urges to hair pull. Ms. A hasexperienced weight loss of approximately 5 lbs which she reports as apositive side effect. Possible other side effects of topiramateadministration include disruption of attention and concentration andcognitive deficits such as word finding difficulties.

Ms. A has been evaluated psychometrically for these side effects.Results from the Delay task of the Gordon Diagnostic System, a widelyused measurement of impulse control, have shown improvements frombaseline (FIG. 17). Subsequent testing of word finding abilities throughthe Control Oral Word Association Test (COWAT) and Semantic CategoryNaming test have shown no significant changes from baseline (FIG. 18).

The patient has continued to see a reduction in the urge to, as well asin the time, spent, pull her hair. Re-growth of hair at the sitespreviously pulled has also been observed. The patient is currently on475 mg topiramate (p.o. q.h.s.).

EXAMPLE 7 Effects of Topiramate on Trichotillomania

A 19-year-old female with a history of trichotillomania and skin pickinghas also been treated in accordance with the invention. She presentedwith skin lesions on her hands and face that resulted from picking atpimples (face) and pulling of hair on the backs of her hands. Severalmedications, in various classes, were previously tried withoutimprovement (including mirtazapine, citalopram, gabapentin, paroxetine,nefazadone, and sertaline). The initiation of topiramate has resulted inthe resolution of her trichotillomania, with noticeable re-growth ofhair on the backs of her hands at 200 mg. p.o. q.h.s.) and has alsoresulted in improvements in the facial skin lesions. She is currently on300 mg q.d. topiramate monotherapy.

1. A method of treating dermatological injury or tissue damagecomprising: a) providing an individual having a dermatological injury ortissue damage; and b) administering, to said individual, atherapeutically effective amount of a composition comprising a carrierand an anticonvulsant agent of the formula:

wherein X₁ is CH₂ or oxygen; R₁ is hydrogen or alkyl; and R₂, R₃, R₄,and R₅ are independently hydrogen or lower alkyl and, when X₁ is CH₂, R₄and R₅ can combine to form a benzene ring and when X₁ is oxygen, R₂ andR₃ and/or R₄ and R₅ together may be a methylenedioxy group of thefollowing formula:

wherein R₆ and R₇ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.
 2. The method according to claim 1, wherein said composition istopically administered, orally administered, parenterally administeredor administered via injection.
 3. The method according to claim 1,wherein said composition comprises a salve, ointment, aerosol, cosmetic,liquid, tablet, powder, capsule, or bioadhesive.
 4. The method accordingto claim 1, wherein said composition is administered as a component of abandage, transdermal patch, wound dressing, cosmetic, or bioadhesive. 5.The method according to claim 2, wherein said composition is topicallyadministered.
 6. The method according to claim 2, wherein saidcomposition is orally administered.
 7. The method according to claim 2,wherein said composition is parenterally administered.
 8. The methodaccording to claim 2, wherein said composition is administered viainjection.
 9. The method according to claim 1, wherein theanticonvulsant agent of Formula I is topiramate(2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate). 10.The method according to claim 9, wherein the dosage of topiramate is: a)0.1 mg to about 400 mg; b) about 10 mg to about 200 mg; c) about 20 mgto about 100 mg; or d) about 25 mg.
 11. A method of promoting woundhealing comprising: a) providing an individual having a wound; and b)administering, to said individual, a therapeutically effective amount ofa composition comprising a carrier and an anticonvulsant agent of theformula:

wherein X₁ is CH₂ or oxygen; R₁ is hydrogen or alkyl; and R₂, R₃, R₄,and R₅ are independently hydrogen or lower alkyl and, when X₁ is CH₂, R₄and R₅ can combine to form a benzene ring and when X₁ is oxygen, R₂ andR₃ and/or R₄ and R₅ together may be a methylenedioxy group of thefollowing formula:

wherein R₆ and R₇ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.
 12. The method according to claim 11, wherein said composition istopically administered, orally administered, parenterally administeredor administered via injection.
 13. The method according to claim 11,wherein said composition comprises a salve, ointment, aerosol, cosmetic,liquid, tablet, powder, capsule, or bioadhesive.
 14. The methodaccording to claim 11, wherein said composition is administered as acomponent of a bandage, transdermal patch, wound dressing, cosmetic, orbioadhesive.
 15. The method according to claim 12, wherein saidcomposition is topically administered.
 16. The method according to claim11, wherein the anticonvulsant agent of Formula I is topiramate(2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate). 17.The method according to claim 16, wherein the dosage of topiramate is:a) 0.1 mg to about 400 mg; b) about 10 mg to about 200 mg; c) about 20mg to about 100 mg; or d) about 25 mg.
 18. A method for treating orcontrolling neurogenetic disorders in an individual comprising theadministration of a therapeutically effective amount of a compositioncomprising an anti-convulsant agent and a pharmaceutically acceptablecarrier; wherein said neurogenetic disorders are selected from the groupconsisting of hereditary ataxias and related disorders, Friedreichataxia, ataxia telangiectasia, olivopontine cerebellar degeneration,Ramsay Hunt syndrome, abetalipoproteinemia, Machado-Joseph disease,familial spastic paraparesis, movement disorders, juvenile Huntingtondisease, dystonias, blepharospasm, spasmodic torticolis, tremor,myoclonus, Hallervorden-Spatz disease, phakomatoses, neurocutaneoussyndromes, neurofibromatosis, tuberous sclerosis, Sturge-Weber, VonHippel-Landau disease, mitochondrial encephalomyopathies, MELASsyndrome, Keams-Sayre, Leigh disease, hereditary disorders of nerve andmuscle, infantile spinal muscular atrophy, Charcot-Marie-Tooth disease,hereditary sensory and autonomic neuropathies, genetic myasthenicsyndromes, metabolic myopathies, muscular dystrophies, myotonias,Laurence-Moon-Bardet-Biedl syndrome, Aicardi, Sjogren-Larsson syndrome,Prader-Willi syndrome, Angelman syndrome, gouging, oppositionalbehavior, and obsessive ruminations.
 19. The method according to claim18, wherein said neurogenetic disorder is obsessive ruminations.
 20. Themethod according to claim 18, wherein said anticonvulsant agent has theformula:

wherein X₁ is CH₂ or oxygen; R₁ is hydrogen or alkyl; and R₂, R₃, R₄,and R₅ are independently hydrogen or lower alkyl and, when X₁ is CH₂, R₄and R₅ can combine to form a benzene ring and when X₁ is oxygen, R₂ andR₃ and/or R₄ and R₅ together may be a methylenedioxy group of thefollowing formula:

wherein R₆ and R₇ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.